α, β-diamino acid is an important compound as a chemical product and a pharmaceutical product. The foregoing α, β-diamino acid has two asymmetric points in its backbone. And, asymmetric synthesis of the α, β-diamino acid is an important task to be studied/researched. By the way, the Mannich-type reaction (carbon-carbon bond forming reaction) between an α-anion equivalent of glycine and imine (or an imine equivalent) is the most efficient technique (Scheme 2-1-1). The reason is that the two asymmetric points being generated can be simultaneously controlled. Yet, the reason is that the α, β-diamino acid backbone having desired configurations can be structured at a time.
A typified example of the Mannich-type reactions using the α-anion equivalent of glycine is shown below.

Soloshonok, Avilov et al. reported the diastereoselective reaction using chiral auxiliaries (a stoichiometric amount of a chiral source). Optically active nickel composites derived from glycine are used for this reaction. And, the highly diastereoselective reaction was realized. The substrate generality is lacking. However, the product can be induced into syn α, β-diamino acid
(Scheme 2-1-2)

Williams et al. reported the diastereoselective reaction using glycine derivatives derived from chiral oxazinone. In any of these examples, the chiral source was introduced into the glycine derivatives, being a nucleophile.
Viso et al. and Davis et al. reported an example of introducing the chiral source into an electrophile (the reaction using chiral sulfinimine as a substituent on nitrogen).
Davis et al. can manufactures a syn-compound and an anti-compound at will by changing a protecting group on nitrogen of glycine derivatives (Scheme 2-1-3).

After O'Donnel et al. synthesized the glycine Schiff base derived from stable benzophenone, the various reactions using this substrate as prochiral glycine derivatives have been rapidly developed. The mono-alkylated products were obtained by using the glycine Schiff base derived from benzophenone. The mono-alkylated products are hardly obtained with the glycine Schiff base derived from aldimines. In addition, putting stability in water into practical use allowed a large number of optically active phase transfer catalysts to be developed. And, it has become possible to manufacture both of D and L-optically active amino acid derivatives at will (Scheme 2-1-4).
This glycine Schiff base derived from benzophenone (the pKa value of α-position hydrogen is approximately 18.7) is easily deprotonated with KOH that is used together with the phase transfer catalyst (Figure 2-1-1).
However, the dialkylation of the Schiff base derived from alanine is suppressed because the pKa value thereof is approximately 22.8.
The asymmetric Mannich-type reaction as well using this glycine Schiff base derived from benzophenone has been developed. Its example is shown below.

Jorgensen et al. reported the addition reaction to N-tosylimines using triethylamine as a base in the presence of a copper complex having a chiral ligand (Scheme 2-1-5).
Herein, effectiveness is demonstrated in not only aromatic imines but also imines derived from aliphatic aldehydes. In either case, the obtained α, β-diamino acid derivatives exhibits the high enantioselectivity. However, using the aromatic imines causes the diastereoselectivity to decline slightly. As a rule, it is difficult to remove a tosyl group, being a protecting group of the amino group.

Maruoka et al. reported the various reactions (for example, the asymmetric alkylation of the glycine Schiff base derived from benzophenone) using the chiral phase transfer catalyst developed on their own. For example, the Mannich-type reaction for α-iminoester was reported (Scheme 2-1-6). This reaction affords 3-amino aspartic acid derivatives. However, the active α-iminoester has to be used as an electrophile. For this, the problem remains in terms of the substrate generality.

Shibasaki et al. reported the Mannich-type reaction (the phase transfer catalyst: an optically active diammonium salt derived from tartaric acid) for N-Boc imine (Scheme 2-1-7). Not only the aromatic imines but also the imines derived from aliphatic aldehydes were reported herein. And, the wide-range substrate generality is shown. In this reaction, syn α, β-diaminoester derivatives are highly selectively obtained.

This inventor et al. as well has studied the Mannich-type reaction using the glycine Schiff base (Scheme 2-1-8).
With this reaction, the deprotonation is conducted with enamine (having the Lewis acid activated glycine Schiff base as a substrate). And, enolate is generated. This reaction is a reaction of conducting a nucleophilic addition reaction for iminium that is co-generated (a reaction requiring no external base). Further, this inventor et al. conducted the development into the asymmetric reaction with Me-DUPHOS defined as a chiral ligand. This reaction has a problem that should be solved, namely, a problem of the diastereoselectivity. However, the obtained target product exhibits the high enantioselectivity. It was reported that applying this reaction to a three-component Mannich-type reaction allowed the obtained adduct to exhibit the high diastereoselectivity. In this reaction, the anti-product is obtained as a main product differently from the other Mannich-type reactions. And, it is of interest from a viewpoint of the reaction mechanism.

Above, examples of the reports of the catalytically asymmetric Mannich-type reactions using the glycine Schiff base derived from benzophenone were mentioned.
However, the room for further improvement is left hereto in terms of the selectivity, the substrate generality, etc.
One equivalent of the metal bases or more such as KOH used together with the phase transfer catalyst is used. Thus, the above reaction is not satisfactory as an environment-friendly reaction.
Jorgensen et al. reported that the deprotonation was difficult with a catalyst amount of organic amines (tertiary amines) (Scheme 2-1-9).

There are many reactions other than the Mannich-type reactions where the deprotonation is rate-limited. Ishikawa et al. reported the Michael reaction using chiral guanidine (Scheme 2-1-10). This reaction exhibits the high enantioselectivity. And, the catalyst is collected. However, the excessive substrate has to be used. Further, a progress of the reaction is slow. Thus, the development of the high reactive substrate is desired.

Fluorene is more stable in terms of the conjugate base after the deprotonation as compared with diphenylmethane. And, acidity of the 9-position hydrogen is very high (Figure 2-1-2).
Carpino et al. reported a Fmoc group as a protecting group of the amino group by utilizing this properties. While this Fmoc group is not broken under the acid condition that is used at the moment of breaking a Boc group, it is easily broken with the relative weak base such as secondly amine. And, the Fmoc group is used in not only solid-phase synthesis of peptides but also synthesis of natural products because it is selectively deprotectable (Scheme 2-1-11).
This inventor thought that the reactivity of the substrate was able to be raised by utilizing a unique property that this methine anion is stable.


At first, a concept of the glycine Schiff base derived from fluorenone imine will be described.
α-position hydrogen of the glycine alkyl ester derived from benzophenone exhibits very high acidity as compared with α-position hydrogen of the general esters (Figure 2-1-3).

This is owing to an electron withdrawing effect of the α-position Schiff base portion.
It is thought that the electron withdrawing of the Schiff base portion has a correlation with stability of a resonance structure of the methine anion.
Thereupon, this inventor used the glycine Schiff base derived from fluorenone (which is thought to be stable due to a contribution by the resonance structure having flatness, and having 14π-electron aromaticity) for the corresponding conjugate base. That is, it was thought that the glycine Schiff base derived from fluorenone promoted the deprotonation of the α-position hydrogen all the more, and developed the Mannich-type reaction more smoothly than the base derived from benzophenone (Figure 2-1-4).

As a matter of fact, as shown below, some reports say that the acidity of the α-position hydrogen of the fluorenone imine is very higher than that of the benzophenone imine (The former differs from the latter by approximately ten times in terms of the pKa value in a DMSO solution (Figure 2-1-5).

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